Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma.

Area of Science:

• Dermatology
• Oncology
• Molecular Biology

Background:

• Basosquamous carcinoma (BSC) presents aggressive features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).
• Genetic drivers for BCC and SCC are known, but BSC's origin and molecular pathways remain unclear.
• Understanding BSC's genomic landscape is crucial for elucidating its derivation and reprogramming mechanisms.

Purpose of the Study:

• To characterize genomic alterations in sporadic BSC.
• To determine the cellular origin of BSC.
• To identify molecular pathways involved in BSC phenotype reprogramming.

Main Methods:

• Genomic alteration analysis in BSC samples.
• Principal component analysis of BCC and SCC driver genes.
• Evolutionary analysis of mutation timing.
• Analysis of mitogen-activated protein kinase (MAPK) and Hedgehog (Hh) signaling pathways.

Main Results:

• Frequent Hedgehog (Hh) pathway mutations identified, implicating Hh deregulation as a primary driver.
• Principal component analysis showed genetic similarity between BCC and BSC.
• Recurrent ARID1A mutations found in 45% of BSCs, occurring after PTCH1 mutations but before SCC drivers.
• MAPK pathway activation and loss of Hh signaling correlate with BSC squamatization.

Conclusions:

• Results support the derivation of BSC from BCC.
• ARID1A mutations likely confer plasticity, enabling tumor reprogramming.
• These findings illuminate factors modulating phenotype switching in BSC.